The rapidly increasing use of drugs in the treatment of psychiatric patients constitutes an unknown hazard to the health of the present and of future generations. The objectives of the proposed research are to assess whether or not two widely used psychotropic drugs, chlorpromazine and imipramine produce detectable chromosome damage and to conduct the investigation in such a way that it can serve as a format for further studies of the mutagenic effects of drugs. For these purposes the following techniques have been combined: (1) single-blind examination of chromosomes in cultured peripheral leukocytes of patients before and during drug therapy, of unmedicated control patients, of non-patient controls and of patients' relatives; (2) long-term follow-up of all the above groups to determine degree of stability or variability of chromosome findings; (3) comparison of the in vitro drug effect upon chromosomes of genetically related (parents, siblings) and unrelated persons in order to detect genetically determined differences in susceptibility to chromosome damage upon exposure to given drugs; (4) comparison of in vivo and in vitro drug effects, using peripheral leukocytes from the same individuals, in order to detect the presence or absence of a consistent relationship; (5) comparison of effects upon chromosomes of acute and chronic drug administration in another mammal (rat) with those in man and (6) in the rat comparison of effect upon somatic chromosomes with that upon germinal cells and upon progeny; (7) detection of mutagenic effects other than grossly visible chromosome damage through use of the dominant lethal test in rats; (8) long-term follow-up of rat progeny (at least three generations) for teratogenicity and neoplasia. Fulfillment of these objectives will represent a first step on the way toward assessing the genetic hazard of these psychotropic drugs.